1. Field of the Invention
The present invention relates generally to the field of treatment of diabetes mellitus. More particularly, it concerns methods of diagnosing a propensity for type 2 diabetes mellitus, methods of identifying compounds to treat type 2 diabetes mellitus, and new nucleic acid sequences encoding polypeptides related to type 2 diabetes mellitus.
2. Description of Related Art
Diabetes mellitus is a phenotypically and genetically heterogeneous group of metabolic diseases all of which are characterized by high blood glucose levels resulting from an absolute or relative deficiency of the hormone insulin (The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 1997). The chronic hyperglycemia damages the eyes, kidneys, nerves, heart and blood vessels leading to blindness, kidney and heart disease, stroke, loss of limbs and reduced life expectancy. Diabetes mellitus is a major public health problem affecting more than 120 million people worldwide (King et al., 1998). It has an enormous economic impact on society and the direct medical and indirect expenditures attributable to diabetes in 1997 in the United States alone were $98 billion (American Diabetes Assoc., 1998).
Genetics play an important role in the development of diabetes with some forms resulting from mutations in a single gene whereas others are oligogenic or polygenic in origin. The monogenic forms of diabetes may account for 5% of all cases of diabetes and have diverse causes. Diabetes can result from mutations in the insulin (Steiner et al., 1995) and insulin receptor genes (Taylor et al., 1995) as well as the genes encoding the glycolytic enzyme glucokinase (Vionnet et al., 1992) and the transcription factors hepatocyte nuclear factor-1.alpha. (HNF-1.alpha.), HNF-1.beta., HNF-4.alpha. and insulin promoter factor-1 (IPF-1) (Yamagata et al., 1996a; Horikawa et al., 1997; Yamagata et al., 1996b; Stoffers et al., 1997). Mutations in these genes lead to impaired pancreatic .beta.-cell function or in the case of the insulin receptor to defects in insulin action in target tissues including the pancreatic .beta.-cell. In addition to these nuclear-encoded genes, mutations in maternally-inherited mitochondrial genes can cause diabetes and appear to do so primarily by impairing pancreatic .beta.-cell function (Maassen and Kadowaki, 1996).
The two most common forms of diabetes, type 1 and type 2 diabetes, have a complex mode of inheritance. Type 1 diabetes is a common chronic disorder of children which accounts for about 5-10% of all diabetes. It results from the autoimmunological destruction of the insulin-producing cells of the pancreas leading to an absolute deficiency of insulin and requirement of insulin therapy for survival. Type 1 diabetes was the first genetically complex disorder to be studied by large-scale genome-wide screening for susceptibility genes and these studies showed the importance of the HLA region in determining susceptibility and revealed the locations of other loci with smaller effects on susceptibility (Davies et al., 1994; Hashimoto et al., 1994; Lernark and Ott, 1998).
Type 2 diabetes is the most common form of diabetes accounting for about 90% of all cases of diabetes and affecting 10-20% of those over 45 years of age in many developed countries. It is characterized by defects in insulin action resulting in decreased glucose uptake by muscle and fat and increased hepatic glucose production, and by abnormalities in the normal pattern of glucose-stimulated insulin secretion. Type 2 diabetes results from the joint action of multiple genetic and environmental factors. Linkage studies have led to the localization of susceptibility genes for type 2 diabetes in Mexican Americans (Hanis et al., 1996), in the linguistically-isolated Swedish-speaking population living in the Botnia region on the western coast of Finland (Mahtani et al., 1996), and in the Pima Indians of the southwestern United States (Pratley et al., 1998). Each study localized susceptibility to largely different regions of the genome suggesting that different combinations of susceptibility genes are responsible for type 2 diabetes in these various populations.
Genome-wide screens for susceptibility genes for complex disorders have become de rigueur and genes for a number of different complex disorders have been successfully localized through linkage studies. Although disease genes for complex disorders can be localized through genetic studies, their identification still represents a major challenge if there are no candidates in the region of interest. This is due in part to the fact that recombination events cannot be used to unambiguously define the boundaries of the region containing the susceptibility locus because of heterogeneity within and between families. The location of a gene for a complex disorder is defined by a confidence interval which may be and often is quite large. The future of genetic studies of complex disorders depends on the ability to identify predisposing genes once they have been mapped.
There are no examples of the successful identification of a gene for a complex disease originally mapped by linkage that can be used to guide such studies. It has been proposed that linkage disequilibrium mapping can be used to refine the localization and perhaps identify the disease locus (Spielman and Ewens, 1998). However, it is unclear how successful linkage disequilibrium mapping will be when only affected sibpairs are available for study as is the case for many common late-onset disorders such as type 2 diabetes.
Moreover, experience in identifying genes for complex disorders is so limited that it is not known whether the susceptibility is due to only one or a few variants or many. The presence of a large number of disease-associated variants would confound linkage disequilibrium studies. Thus, there is a need to provide an exemplary protocol for the identification of genes in complex disorder and further, there is a pressing need to identify the elusive type-2 diabetes susceptibility gene. Despite the desirablity of these endeavors these needs remain unfulfilled.